Cotadutida (agonista duplo GLP-1/glucagon) afeta o pâncreas, tecido adiposo marrom e hipotálamo de camundongos obesos

Abstract

Obesity and Type 2 Diabetes Mellitus (T2DM): A Multifaceted Impact. Obesity combined with T2DM induces profound alterations in alpha- and beta-cells, brown adipose tissue (BAT), and hypothalamic neuropeptides. Beta cells, as key regulators of insulin production, remain a primary target for cell replacement and regenerative therapies aimed at treating T2DM. Current strategies focus on enhancing beta-cell proliferation and promoting functional maturity. Meanwhile, an emerging therapeutic avenue involves reprogramming various cell types into insulin-producing cells. Among these, alpha cells stand out as promising candidates due to their phenotypic similarity to beta cells and their genomic accessibility for transdifferentiation. Cotadutide: A Novel Dual GLP-1/Glucagon Receptor Agonist. Cotadutide, a novel dual GLP-1/glucagon receptor agonist, holds potential for improving islet cell architecture and function, remodeling interscapular BAT, enhancing thermogenesis, and modulating hypothalamic neuropeptides. This study explored the effects of cotadutide in obese mice. Twelve-week-old male C57BL/6 mice were fed either a control diet (C, 10% kJ fat) or a high-fat diet (HF, 50% kJ fat) for ten weeks. Subsequently, the animals were divided into four groups and treated daily for 30 days with subcutaneous injections of cotadutide (30 nmol/kg) or vehicle: C, CC (control + cotadutide), HF, and HFC (high fat + cotadutide). Key Findings and Effects of Cotadutide. Cotadutide administration in the HFC group resulted in significant weight loss and improved insulin sensitivity. These benefits were evidenced by increased expression of insulin receptor substrate 1 and solute carrier family 2 in isolated pancreatic islets. Additionally, cotadutide enhanced transcription factors associated with islet cell transdifferentiation and alleviated markers of endoplasmic reticulum (ER) stress. In BAT, cotadutide reversed adipocyte hypertrophy, structural disarray, and lipid accumulation observed in the HF group. Furthermore, cotadutide promoted thermogenesis, increased body temperature, enhanced angiogenesis and lipolysis, and stimulated mitochondrial biogenesis. In the hypothalamus, cotadutide treatment in the HFC group improved the expression of genes linked to energy balance and associated signaling pathways, indicating modulation of the gut-brain axis. Conclusions and Implications. In conclusion, this study demonstrates that cotadutide exerts profound benefits in obese mice, including weight reduction, enhanced glycemic control, and improved insulin sensitivity. Cotadutide also ameliorated adverse remodeling of pancreatic islets by improving markers of transdifferentiation, proliferation, apoptosis, and ER stress. Additionally, its thermogenic effects on interscapular BAT and its role in energy balance modulation through the gut-brain axis provide new insights into its mechanisms of action. These findings highlight the potential translational benefits of cotadutide for addressing obesity and T2DM.